Background: Lung cancer is the number one cause of cancer death in men and women in the United States and remains an identified medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel. Recent data shows an actual increase in smoking rates among active military personnel and smoking rates among Veterans are consistently at least 10% higher than the general population (29% vs. 18%). The five-year survival rate for lung cancer remains 16%, a rate which has shown limited improvement over the last several decades. Among Veterans, only 16% of lung cancer is currently diagnosed at a curable stage. Large-scale screening trials (most notably the National Lung Screening trial - NLST) have been completed, and low dose CT scans were proven to significantly decrease lung cancer mortality (20%) when compared to chest x-ray. CT screening for lung cancer has been endorsed by many groups and a VA implementation study is being conducted. If CT screening is widely adopted in high risk groups (as defined by the NLST), there should be an increase in patients presenting with curable disease (stages I and II), leading to improved overall survival. Improved survival will result in a growing population of patients at ris for second primary lung cancers. The risk of developing a second primary lung cancer after curative treatment ranges from 3-6%. Former smokers are also at high risk of lung cancer, with greater than 50% of lung cancers in the US diagnosed in this group. The potential clinical impact of chemopreventive agents in this large, high-risk population emphasizes the need for continued studies. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemopreventive strategies. Work Accomplished: Prostacyclin (prostaglandin I2, PGI2) is a naturally occurring eicosanoid that possesses anti-inflammatory and anti-metastatic properties, as well as a suppressive role in tumor growth. We have found that the balance of these eicosanoids is pivotal in lung tumorigenesis and key mechanistic studies completed during the last grant cycle have shown that the observed chemoprevention may directly result from PGI2 and PGI2 analogues engaging the transcription activator PPAR (peroxisome proliferator activated receptor gamma). These findings, coupled with clinical studies observing a 33% reduction in lung cancer rates among Veterans taking PPAR agonists for diabetes mellitus, suggest PPAR agonists may prevent lung cancer. My VA funded laboratory has focused on evaluating PGI2 as a chemopreventive agent, and animals with increased levels of PGI2 or receiving PPAR agonists are protected from developing lung cancer. Most importantly, this led to a phase II clinical trial which showed oral iloprost improved endobronchial damage in former smokers. Our current human trial is evaluating pioglitazone is high risk current and former smokers. Proposed Research: This grant proposes to advance pre-clinical studies of PPAR agonists in a squamous cell lung cancer model with a focus on the effects of PPAR agonists on the tumor microenvironment (TME) and macrophage programming. We hypothesize that PPAR activators (endogenous PGI2 and pioglitazone) will chemoprevent the development of endobronchial dysplasia and lung tumors, and will alter the TME by affecting inflammatory cell recruitment and phenotype. The following hypotheses will be tested: Hypothesis 1: PPAR agonists promote anti-tumor effects by influencing the production of pro- and anti- growth factors by tumor associated macrophages. Hypothesis 2: Selective PPAR agonists (endogenous prostacyclin and pioglitazone) chemoprevent the development of murine squamous cell lung cancer and pre-malignant endobronchial dysplasia by altering inflammatory cell populations and macrophage phenotype.